N-adamantyl amides

ABSTRACT

Adamantyl lactams are prepared by reacting an adamantyl amine with a 3-, 4-, or 5-halo acyl halide to yield an adamantyl amine haloamide followed by base cyclization of the latter. These adamantyl lactams possess antiviral and antibacterial activities.

United States Patent [72] Inventors SeymourD.Levine;

Venkatachala L. Narayanan, both of North Brunswick, NJ. [2l] Appl. No. 15,205 [22] Filed Feb. 27, 1970 [45] Patented Nov. 30, 1971 [73] Assignee E. R. Squibb & Sons, Inc.

New York, NY.

Continuation-impart of application Ser. No. 837,000, June 26, 1969, now abandoned. This application Feb. 27, 1970, Ser. No. 15,205

[54] N-ADAMANTYL AMIDES 2 Claims, No Drawings 521 0.5. CI 260/465 0, 260/239 A, 260/514 B, 260/544 L, 260/557 R,

260/557 B, 260/558 R, 260/558 A, 260/559 R,

260/559 D, 260/559 P, 260/561 HL, 260/563 P,

[5!] 161.01 ..C07C103/30, C07C 103/32, C07d 25 02 50 Field 6: Search 260/465 D.

561 HL, 557 R, 558 R. 558 A, 559 R, 559 D, 559 P Primary ExaminerAlton D. Rollins Almrneys- Lawrence S. Levinson, Merle J. Smith, Theodore J. Criares, Donald J. Perrella and Burton Rodney ABSTRACT: Adamantyl lactams are prepared by reacting an adamantyl amine with a 3-, 4-, or S-halo acyl halide to yield an adamantyl amine haloamide followed by base cyclization of the latter. These adamantyl lactams possess antiviral and antibacterial activities.

N-ADAMANTYL AMIDES SUMMARY OF THE INVENTION This invention relates to new compounds of the formula l RI wherein R and R are the same or different and are H, lower alkyl or lower alkoxy, n is an integer from O to 4, and R" and R' are the same or different and are H, a straight or branched chain alkane of up to eight carbon atoms or a phenyl substituted alkane or a substituted-phenyl substituted alkane, of up to carbon atoms, phenyl, or alicyclic of up to eight carbon atoms, and m is an integer from I to 3.

DETAILED DESCRIPTION The compounds of the present invention are obtained by reacting a compound of the formula wherein R and R are the same or different and are H, lower alkyl or lower alkoxy, n is an integer from O to 4, with a halo-acyl halide of the formula (III) wherein X is Cl or Br and R" and R' are the same or dif ferent and are H, a straight or branched chain alkane of up to eight carbon atoms or phenyl substituted alkane or a substituted phenyl substituted alkane, of up to 10 carbon atoms, phenyl, or alicyclic of up to eight carbon atoms, and s is an integer from 0 to 2.

For R and R, the lower alkyl groups include straight or branched chain aliphatic hydrocarbon radicals of up to six carbon atoms. Examples of such lower alkyl groups are the following radicals: methyl, ethyl, propyl, i-propyl, n-butyl, ibutyl, n-pentyl, neopentyl, 2-methyl-n-butyl, n-hexyl, 2- methyl-n-pentyl, B-methyI-n-pentyl, 2,2-dimethyl-n-butyl, and 2,3-dimethyl-n-butyl. The lower alkoxy groups similarly include straight or branched chain aliphatic oxyhydrocarbon radicals containing up to six carbon atoms. Examples of such lower alkoxy groups are those corresponding to foregoing lower alkyl radicals.

For R" and R', the straight or branched chain alkane includes such groups as, for example, methyl, ethyl, n-propyl, ipropyl, n-butyl, i-butyl, n-pentyl, Z-methyI-n-butyl, neopentyl,

n-hexyl, Z-methyI-n-pentyl, 3-methyl-n-pentyl, 2,2-dimethyln-butyl, 2,3-dimethyl-n-butyl, n-heptyl, Z-methyI-n-hexyl, 3- methyl-n-hexyl, 2,2-dimethyl-n-pentyl, 2,3-dimethyl-n-pentyl, 2,4-dimethyl-n-pentyl, 3,3-dimethyl-n-pentyl, 3-ethyl-n-pen' tyl, 2,2,3-trimethyl-butane, n-octyl, Z-methyI-n-heptyl, 3- methyI-n-heptyl, 4-methyl-n-heptyl, 2,3-dimethyI-n-hexyl, 2,4-dimethyl-n-hexyl, 2,5-dimethyl-n-hexyl, 2,2-dimethyl-nhexyl, 3,3-dimethyl-n-hexyl, Z-ethyI-n-hexyl. 3-ethyl-n-hexyl, 2,2,3-trimethyl-n-pentyl, 2,2,4-trimethyI-n-pentyl, 2,3,3- trimethyl-n-pentyl, 2,3,4-trimethyl-n-pentyl, 2-ethyl-3- methyI-n-pentyl, 2-methyl-3-ethyl-n-pentyl, and 2.2.3.3- tetramethyl-n-butyl. Alicyclic substituents for R" and R' include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l,ldimethylcyclopentyl, l-methyl-cyclohexyl, l,2-dimethylcyclohexyl, cycloheptyl and cyclooctyl. Phenyl substituted ulkanes include benzyl an phenethyl. The total number of carbon atoms in both groups R" and R', however, should not exceed about 12.

In the case of phenyl-substituted alkanes, the phenyl radical may itself be substituted by such groups as halogen, lower alkane and lower alkene, lower haloalkyl, lower alkoxy, lower alkylamino, nitro or cyano. Examples of some specific substituted phenyl radicals are: fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, tolyl, trifluorotolyl, vinylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, N-methyl anilino, N-dimethyl anilino, nitrophenyl and cyanophenyl.

The product obtained by reacting a compound of formula II with a compound of formula III is an adamantylamine haloamide of the formula wherein R, R, n, R", and R' and s are as defined above. Base cyclization of compound IV yields the compounds I of the present invention. Bases which may be used to effect cyclization include sodium in liquid ammonia; sodium hydride in dimethylsufoxide; sodium hydride in dimethylformamide; potassium t-butoxide in toluene; and potassium t-butoxide in benzene.

The adamantyl amine compounds offormula II wherein n is other than 0 may be prepared by reduction of the corresponding amide with lithium aluminum hydride.

The adamantane carboxylic acid amide wherein n is I may be prepared by reacting l-adamantane carboxylic acid with thionyl chloride to form the l-adamantane acid chloride, and reacting the latter with ammonia to form the amide, The amide in turn is reduced, for example, by LiA l H, to the l-ada mantylmethylamine.

l-Adamantyl ethylamine wherein n is 2 may be prepared, for example, by reacting l-bromoadamantane with l,ldichloroethylene in the presence of BB. The resulting l-adamantyl acetic acid is then converted to the amide in the manner described above and the latter reduced, for example, by means of lithium aluminum hydride.

l-Adamantyl propylamine wherein n is 3 may be prepared, for example, starting from l-adamantyl acetic acid, by homologation to l-adamantyl propionic acid according to the method described by Bachmann et al., Organic Reactions, Vol. 1, Chapter 2, and then conversion to the corresponding amine as described above.

l-Adamantyl butylamine wherein n is 4 may be prepared, for example, in like manner starting with l-adamantyl propionic acid.

Compounds of formula I wherein m is 1 may be prepared by reacting a compound of formula II with a 3-halo-acyl halide,

that is, a compound of formula 111 wherein s is to form an adamantyl amine haloamide followed by base cyclization of the latter. Compounds of formula 1 wherein m is 2 may be prepared by reacting a compound of formula 11 with a 4-haloacyl halide, that is, a compound offormula Ill wherein s is l to form an adamantyl amine haloamide followed by base cyclization of the latter. Compounds of formula l wherein m is 3 may be prepared by reacting a compound of formula II with a 5- halo-acyl halide, that is, a compound of formula 111 wherein s is 2 to form an adamantyl amine haloamide followed by base cyclization of the latter.

The following examples illustrate the present invention without, however, limiting the same thereto.

EXAMPLE 1 1 -Adamanty1methylamine 1. Preparation of l-adamantane carboxylic acid chloride To 18 g. of l-adamantane carboxylic acid, 50 ml. of thionyl chloride is added with cooling, and the mixture is heated under reflux for 30 minutes. The excess thionyl chloride is removed in vacuo. Anhydrous ether is added and the solution evaporated leaving 19.2 g. (79.2 percent) of l-adamantane carboxylic acid chloride as a brownish white solid; A,,,,,,,' 5.61 p. (C=O ofacid chloride). 2. Preparation of l-adamantanecarboxamide 1-Adamantane carboxylic acid chloride (35 g.) dissolved in 70 ml. of dry tetrahydrofuran, is added to a cooled aqueous ammonia solution. A white precipitate separates and the mixture is then stirred for 0.5 hours. The precipitate is filtered, washed with water and dried over P 0 in vacuo to give 30.1 g. of l-adamantanecarboxamide; m.p. l86l87.5 5.95 p. (C=O ofamide). 3. Preparation of l-adamantylmethylamine To a stirred suspension of 30 g. of lithium aluminum hydride in 1,000 ml. of ether, 27 g. (0.15 mole) of l-adamantanecarboxamide is added in portions over a 1.5 hour period. The reaction mixture is stirred at room temperature for 1 hour, then refluxed with stirring for 4 hours and finally allowed to stand overnight at room temperature. The suspension is cooled and 50 ml. of water are added dropwise with stirring. This is followed by the addition of 100 ml. of percent sodium hydroxide solution. The ethereal layer is separated and the solid is extracted three times with ether. The combined ethereal layer is dried and evaporated in vacuo to give 14.5 g. of l-adamantylmethylamine as a pale yellow liquid.

EXAMPLE 2 2-( 1-Adamantyl)-ethylamine 1. Preparation of l-Adamantylacetic acid A solution of 25 g. of l-bromoadamantane in 100 g. of dichloroethylene is added dropwise over a 1.5 hour period to 100 ml. of 90 percent sulfuric acid containing 18 g. of borontrifluoride while maintaining the temperature between 8-l0. The mixture is then stirred at 10 for 3 hours, then ice and water are added. The crude precipitate is dissolved in 10 percent sodium hydroxide solution and the cloudy solution extracted with ether. The alkaline solution is cooled, acidified with 5 percent hydrochloric acid, and the precipitated l-ada- 2. Preparation of l-Adamantaneacetie acid chloride This is prepared in the same manner as l-adamantane carboxylic acid chloride (example 1, 1) except that l-adaman- 'taneacetic acid is employed as the starting material.

EXAMPLE 3 N-( 1-Adamantyl)-3-bromopropionamide To 15.1 g. (0.1 mole) of l-aminoadamantane dissolved in 500 ml. of dry benzene, a solution of 17.1 g. (0.1 mole) offlbromopropionyl chloride in 50ml. of dry benzene is added with cooling. The reaction mixture is stirred and refluxed for 2 hours. After cooling, the reaction mixture is washed with water, dilute hydrochloric acid, sodium bicarbonate solution, and water. The benzene layer is dried (MgSO and evaporated to give an oily residue which solidifies on trituration with ether, 12.3 g., m.p. l31-133. Crystallization from acetonitrile gives 8.3 g. of shiny white crystals, m.p. l34-135 A 2.95 p. (NH), 6.05 p. (C=O).

EXAMPLE 4 1-( 1-Adamantyl)-2-azetidinone using ethyl acetate as the developing solvent and elution of the more polar major product with ethyl acetate-methanol (4:1) gives 234 mg. of l-( 1-adamantyl)-2-azetidinone, AKBr 5.75 a;

7.25 (q 3CH and 6.86 (q4-CH The analytical sample is prepared by evaporative distillation to give an oil, which solidifies on standing, m.p. 43.545.5.

Anal. Calcd. for C H NO (205.30)

Found:

EXAMPLES 5-48 The following adamantyl and adamantyl alkyl-3-halo propionamides are prepared by reacting the indicated adamantylacetic acid collected and dried to give 21.5 g. of white mantane derivative with the indicated 3-halopropionylhalide solid, mp. l30-133.

according to the procedure of example 3:

TABLE 1 Example Adamantane derivative 3-halopropi0nyl halide Product 5 l-adamantylamine 3-bromopropionylchloride N(1-adamantyD-3-bromopropiouamide. (L 1nuiumantyimethylmniue.. 2-methyl-3-bromopropiony1 chloride N (LadamantylmehtyD-Z-methyl-B- bromopropionamide. 7 1-adnmantylethylamiuo 2,241imetliyl-S-bromopropionyl chloride"... N (1'adamnntylethyl)-2,2-dimethy1-3-bromopropionamide. s i-ndnmantyl-n-propylmninc 'Z-ethyl-3-bromopriopiouy1 chloride N (1-adamautyl-n-propyl)-2-ethyl-3-bron1opr0pionamide. w i-:ui:unnntyl-n-imtylmninv 2-methyl-Qrthyl-Sbromopropionylchloride. N (1-adamantyl-n-butyl)-2-niethyl-2-ethyl-3-bromopropiouamido.

ing the indicated adamantane derivative with the indicated halo and halide according to the procedure of example 3:

agents, e.g., against influenza virus such as A-PR8 or hepatic virus such as MHV They may be administered to a warm blooded animal in accordance with this invention by any convenient route, including orally, or parenterally, that is, subcu- 3-halopropionyl B-Lactam of Formula I wherein m is 1 and wherein: Example amide of No. Ex. No. R R R R 72 28 H H CH; 011E011- CHr- CH2 CH:CH2 73 29 H H -CH H CHz-C Hz 74 a. 30 H H Same as above CH3 CH2 C H2 76 31 H H H CH2 /CH CHz-CH2 32 H H HCJH'I Same as above. 33 H H CnH5CH2 H 34 H H C 01150 Hz C H: 35 H OH; H H 36 C H; C H; H H 37 (321150 H H H 38 H-CHO CHJO H H 39 H H H 84 40 H H H -cm-om s5 41 n n 0 OH; H 86 42 H H H (Ill 87 43 H H CH2 NO: H 88 i v 44 II H H C H2-/ C N R! 45 ll ll CH3 ll mi 46 ll ll Cll; ll

C Hr- N\ CH; 91 47 H H C H; CH=CH 92 48 H H H C a TABLE 3 Example N o. Adamantane derivative Halo acyl halide Product l-adamantylamine s l-adamantylethylamine l-adamantylamino 96 3-methyl-l-adamantylamine EXAMPLES 97-100 The following products are obtained the haloamide of table 3 according to the procedure of example 4:

TABLE 4 Lactam of Formula I wherein:

Example mum mama

mam

Wwliiw 4brgmobutyryl chloride. N -(l-adamantyl)-4-bromobutyramide.

-(l-adamantylethyl)-4-bromobutyramide. N -(l-adamantyl)-6-bromovaleramide. N -(3-methyl-l-adamantyl)5bromovaleramide.

tancously, intravenously, intramuscularly, or inby base cyclization of traperitoneally. Administration can also be by vapor or spray through the mouth or nasal passages,

The dosage administered will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effeet desired. Generally, a daily dosage of active ingredient compound will be from about 1 to 200 milligrams per kilogram of body weight, although lower, such as 0.5 milligram, or higher amounts can be used. Ordinarily, from i to 50. preferably 1 to 20, milligrams per kilogram per day in one or more applications per day is effective to obtain the desired result.

The compounds of the present invention can be employed in useful compositions according to the present invention by incorporating the free base or a physiologically acceptable salt thereof in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration, or liquid solutions for parental use, and in certain cases, suspension for parenteral use (except intravenous since, of course, intravenous suspensions of any material are hazardous). In such compositions, the active ingredient will ordinarily always be present in an amount of at least 0.000] percent by weight based on the total weight of the composition and not more than 99 percent by weight.

Besides the compounds of the present invention, the composition will contain a solid or liquid nontoxic pharmaceutical carrier for the active ingredient. Mixtures with one or more pharmaceutically active materials can ofcourse be used.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets. In these capsules, tablets, and powders the pharmaceutical carrier will generally constitute from about 5 percent to about 95 percent and preferably from 25 percent to 90 percent by weight. These dosage forms preferably contain from about 5 to 500 milligrams of active ingredient with from about 25 to 250 milligrams most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including oils of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, cod liver oil, and the like. In general, water, saline and aqueous dextrose (glucose) and related sugar solutions are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions will ordinarily contain from about 0.5 to 25 percent, and preferably about 5 to percent, by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension or syrup, in which the active ingredient or- Iii dinarily will constitute from about 0.5 to 10 percent, and preferably about 2 to 5 percent, by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in REMING- TONS PRACTICE OF PHARMACY by E. W. Martin and E. F. Cook, a well-known reference text in this field.

What is claimed is: l. A compound of the formula ll 0 It" ((llIz)nI I( 7 mmr-cuix RII/ wherein R and R may be the same or different and may be H, lower alkyl or lower alkoxy;

n is an integer from 0 to 4;

R and R' may be the same or different and may be H, a

straight or branched chain alkyl radical of up to eight carbon atoms, a phenyl substituted alkyl radical, or a substituted-phenyl substituted alkyl radical having a total of 10 carbon atoms wherein the phenyl substituent may be halogen, alkyl, alkenyl, haloakyl, alkoxy, alkylamine, nitro or cyano; phenyl; or alicyclic of up to eight carbon atoms;

5 is an integer from 0 to 2; and

X is Cl or Br.

2. A compound according to claim 10, wherein s is 0.

3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,624,124 Dated November 1971 Inventor) Seymour D. Levine and Venkatachala L. Narayanan It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 16, "an" should rea'd and Column 7, lines l-4, should be deleted and should be inserted before line 58.

Signed and sealed this 13th day of June 1972.

(SEAL) Attest: EDWARD M.FLETCHER,JR. RO'BERT GOTTSCHALK Attesting (Jr-ricer- Commissioner of Patents 

2. A compound according to claim 1 wherein s is
 0. 